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Axon degeneration triggered by chemotherapy-induced mitochondrial DNA damage

化疗引起的线粒体 DNA 损伤引发轴突变性

基本信息

批准号：
8717866
负责人：
Matthew John Geden
金额：
$ 2.93万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717866
关键词：
Affect Apoptosis Apoptotic Axon Axotomy Biological Assay Biological Models Bromodeoxyuridine Cancer Patient Cell Nucleus Cells Cessation of life Cisplatin DNA DNA Damage DNA biosynthesis DNA lesion Data Development Dose-Limiting Drug Design Drug usage Energy Metabolism Event Exposure to Functional disorder Generations Genomic DNA Genomics Goals In Vitro Lead Measures Mediating Mediator of activation protein Microfluidics Mitochondria Mitochondrial DNA Mitosis Mitotic Modeling Mus Mutant Strains Mice Nerve Nerve Degeneration Nervous System Trauma Neurologic Neurons Nuclear Numbness Outcome Pain Pathway interactions Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Preparations Phosphotransferases Proliferating Proteins Quality of life Reactive Oxygen Species Research Role Source Stress Technology Testing Wallerian Degeneration apoptotic protease-activating factor 1 axonal degeneration calpain inhibitor cancer therapy caspase-3 caspase-6 caspase-9 cell type chemotherapy inhibitor/antagonist innovation mitochondrial autophagy mitochondrial dysfunction motor control neuronal cell body neurotoxicity novel public health relevance small molecule

项目摘要

DESCRIPTION (provided by applicant): A major dose-limiting factor for many chemotherapeutic drugs is the induction of peripheral neuropathy which can cause significant axon damage and neurological deficits in cancer patients. As chemotherapeutic drugs are designed to primarily affect pathways that are active in mitotic cells, such as mitosis and DNA replication, the fact that many of these drugs induce axon degeneration in postmitotic neurons is unexpected and its mechanisms remain largely unknown. In this proposal, my goals are to focus on the frontline drug cisplatin (a DNA damaging agent which has been clinically been shown to induce peripheral neuropathy) and to investigate the mechanisms by which this genotoxic chemotherapeutic drug specifically induces axon degeneration. Studying axon degeneration independently of neuronal death is important because often chemotherapy-induced peripheral neuropathy results from axonal degeneration without any significant loss of the cell bodies. My innovative approach is to use microfluidic technology which allows me to expose only the axons (and not the cell body) to this DNA damaging drug. Indeed, I have established that exposure of cisplatin to exclusively the axons in microfluidic chambers induces widespread axonal degeneration without affecting the cell bodies in peripheral neurons. In this proposal, I will investigate the mechanism by which cisplatin trigger axon degeneration in the absence of nuclear DNA damage. Specifically, in Aim 1, I will determine whether cisplatin acts on axonal mitochondria to induce mitochondrial DNA damage and dysfunction, leading to axon degeneration. In Aim 2, I will determine the mechanism by which cisplatin induces axon degeneration by focusing on three specific degenerative pathways: the apoptotic, necroptotic, and Wallerian degeneration pathways. My innovative approach of isolating neuronal axons using microfluidic chambers allows me the unique ability to test nuclear damage-independent mechanisms of peripheral neuropathy and provides me an opportunity to uncover unanticipated mechanisms by which chemotherapeutic drugs induce axon degeneration.

描述（由申请人提供）：许多化疗药物的主要剂量限制因素是诱导周围神经病变，其可导致癌症患者的显著轴突损伤和神经功能缺损。由于化疗药物被设计为主要影响有丝分裂细胞中的活性途径，如有丝分裂和DNA复制，因此许多这些药物诱导有丝分裂后神经元轴突变性的事实是出乎意料的，其机制在很大程度上仍然未知。在这个提议中，我的目标是关注一线药物顺铂（一种DNA损伤剂，临床上已被证明会诱导周围神经病变），并研究这种遗传毒性化疗药物特异性诱导轴突变性的机制。研究轴突变性独立于神经元死亡是重要的，因为通常化疗诱导的周围神经病变的结果从轴突变性没有任何显着的损失的细胞体。我的创新方法是使用微流体技术，使我能够只将轴突（而不是细胞体）暴露于这种DNA破坏药物。事实上，我已经确定，顺铂暴露于微流体室中的轴突诱导广泛的轴突变性，而不影响外周神经元中的细胞体。在这个提议中，我将研究顺铂在没有核DNA损伤的情况下触发轴突变性的机制。具体来说，在目标1中，我将确定顺铂是否作用于轴突线粒体，诱导线粒体DNA损伤和功能障碍，导致轴突变性。在目标2中，我将确定顺铂诱导轴突变性的机制，重点是三个特定的退化途径：细胞凋亡，坏死性凋亡和沃勒变性途径。我使用微流体室分离神经元轴突的创新方法使我具有独特的能力来测试周围神经病变的核损伤独立机制，并为我提供了发现化疗药物诱导轴突变性的意外机制的机会。